Goto Shiho, Kondo Fumio, Ikai Yoshitomo, Miyake Mio, Futamura Masaki, Ito Komei, Sakamoto Tatsuo
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Eur J Pharmacol. 2009 Apr 17;608(1-3):91-6. doi: 10.1016/j.ejphar.2009.02.036. Epub 2009 Mar 1.
Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 microg/ml, 50 microl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.
他克莫司软膏用于治疗各种慢性炎症性皮肤病。然而，该软膏对皮肤急性神经源性炎症的作用仍有待充分阐明。局部应用辣椒素和间二甲苯可使皮肤感觉神经释放速激肽，导致皮肤血浆渗漏。我们研究了他克莫司软膏（0.1%）对局部应用辣椒素（10 mM）、间二甲苯（纯品）以及皮内注射化合物48/80（c48/80）（10 μg/ml，50 μl/部位）诱导的皮肤微血管渗漏的影响，实验在两组预先用过量辣椒素或其赋形剂处理的大鼠中进行。伊文思蓝染料的渗漏量反映皮肤血浆渗漏情况。在局部应用他克莫司软膏或其基质8小时后，将辣椒素、间二甲苯或c48/80涂抹于大鼠剃毛的腹部。用辣椒素脱敏分别使皮肤对辣椒素和间二甲苯的反应降低了100%和65%，但对c48/80无影响。无论是否用辣椒素预处理，他克莫司软膏均能显著抑制间二甲苯和c48/80诱导的皮肤反应。然而，局部应用他克莫司并不影响辣椒素诱导的皮肤反应。我们还评估了局部应用辣椒素和间二甲苯以及皮内注射c48/80是否会导致在使用他克莫司治疗的皮肤中肥大细胞脱颗粒。通过显微镜评估肥大细胞脱颗粒情况。局部应用他克莫司仅能显著抑制间二甲苯和c48/80诱导的脱颗粒。我们的数据表明，他克莫司软膏部分抑制间二甲苯和c48/80诱导的大鼠皮肤血浆渗漏和肥大细胞脱颗粒，但不抑制辣椒素诱导的反应，这表明其抑制作用与神经源性介导机制的降低无关。
